Compartment Syndrome Following Snake Envenomation in the United States: A Scoping Review of the Clinical Literature

Introduction Local tissue destruction following envenomation from North American snakes, particularly those within the Crotalinae subfamily, has the potential to progress to compartment syndrome. The pathophysiology of venom-induced compartment syndrome (VICS) is a debated topic and is distinct from trauma/reperfusion-induced compartment syndrome. Heterogeneity exists in the treatment practices of VICS, particularly regarding the decision to progress to fasciotomy. Associations with functional outcomes and evolution in clinical practice since the introduction of Crotalidae polyvalent immune Fab (FabAV) have not been well defined. Our goal was to identify the potential gaps in the literature regarding this phenomenon, as well as illuminate salient themes in the clinical characteristics and treatment practices of VICS. Methods We conducted this systematic scoping-style review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Records were included if they contained data surrounding the envenomation and hospital course of one or more patients who were envenomated by a snake species native to North America and were diagnosed with compartment syndrome from 1980–2020. Results We included 19 papers: 10 single- or two-patient case reports encompassing 12 patients, and nine chart reviews providing summary statistics of the included patients. In case reports, the median compartment pressure when reported was 60 millimeters of mercury (interquartile range 55–68), 66% underwent fasciotomy, and functional outcomes varied. Use of antivenom appeared to be more liberal with FabAV than the earlier antivenin Crotalidae polyvalent. Rapid progression of swelling was the most commonly reported symptom. Among the included retrospective chart reviews, important data such as compartment pressures, consistent laboratory values, and snake species was inconsistently reported. Conclusions Venom-induced compartment syndrome is relatively rare. Existing papers generally describe good outcomes even in the absence of surgical management. Significant gaps in the literature regarding antivenom dosing practices, serial compartment pressure measurements, and functional outcomes highlight the need for prospective studies and consistent standardized reporting.


INTRODUCTION
The venomous snakes of North America capable of causing significant soft tissue damage fall under the family Viperidae and the subfamily Crotalinae (also referred to as crotalids). 1 Snakes in this category consist of the genera Crotalus (rattlesnakes), Sistrurus (pygmy rattlesnake and massasauga), and Agkistrodon (cottonmouth and copperheads).These genera are often colloquially referred to as pit vipers due to the presence of heat-sensing pits behind their nostrils. 2Crotalid venom is a complex mixture of more than 100 macromolecules, glycoproteins, and metals.Phospholipase A2, inflammatory mediator analogues, and metalloproteinases damage endothelium and disrupt normal coagulation cascades, primarily manifesting as local tissue destruction and hematologic toxicity, although neurotoxicity can develop after envenomation from some species. 3,4In severe cases, tissue destruction and swelling due to crotalid envenomation has the potential to progress to compartment syndrome.In contrast, elapid venom found in North American coral snakes results in little to no local tissue destruction. 5,6he nature of venom-induced compartment syndrome (VICS) is a debated topic, as local symptoms common to crotalid envenomation such as pallor, edema, paresthesia, and pain with passive movement can mimic trauma or reperfusion-associated compartment syndrome.6][7] As a result, some advocate against using the term compartment syndrome to describe the condition.Consequently, there is heterogeneity in how clinicians approach suspected cases of VICS, including the role of fasciotomy.
This treatment inconsistency also stems from historic misguidance of suspected cases of compartment syndrome following envenomation, which reached its nadir in the 1970s-1980s when fasciotomy was considered the gold standard of treatment.Numerous reviews and animal models suggest that prompt antivenom administration precludes the need for fasciotomy, as antivenom treatment alone has been shown to reduce intracompartmental pressures in animal models. 8,9In a 2011 review, Cumpston concluded that current evidence did not support the use of fasciotomy in Crotalinae envenomation with elevated compartment pressures and might even worsen outcomes. 7Of note, the majority of articles included in that review describe patients treated with antivenin Crotalidae polyvalent (ACP), prior to the introduction of Crotalidae polyvalent immune Fab (FabAV), adding significance to an additional review.
At our institution, we were recently consulted in two copperhead envenomations in which local tissue damage progressed to alleged compartment syndrome with elevated compartment pressures; fasciotomy was performed in both cases.This led our team to question how often this clinical scenario occurs and what literature exists to guide management and inform prognosis.Therefore, we performed a review of literature reporting compartment syndrome following North American snake envenomation to gather data regarding symptomatology, laboratory/pressure abnormalities, interventions, and outcomes and to identify gaps in the literature surrounding this phenomenon, particularly concerning functional outcomes.

METHODS
We conducted a systematic review of published studies reporting compartment syndrome following North American snake envenomation from January 1, 1980-November 18, 2020.Our team included three medical toxicologists, one resident physician, and an information specialist (librarian MSW).We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement as the guideline for conducting this review. 10According to the guidelines of the Emory University Institutional Review Board, this study was not human subjects research and did not require review.
After consultation with other team members, the information specialist developed a search strategy; six

Population Health Research Capsule
What do we already know about this issue?Compartment syndrome is a rare complication of envenomation by certain snake species; clinical data regarding this phenomenon is poorly described.

What was the research question?
What are the clinical characteristics, treatment paradigms and functional outcomes of venom-induced compartment syndrome (VICS)?
What was the major finding of the study?For 19 papers, the median compartment pressure was 60 mm Hg (IQR 55-68) and 66% underwent fasciotomy.Functional outcomes varied but were generally good.
databases were searched.We searched terms "compartment syndromes," "snake bite," "snake bites," and "North America."The systematic searches were performed in Agricola (Ebscohost), Cochrane Central Register of Controlled Trials (CENTRAL via Cochrane Library), Embase (Elsevier), Global Health (CAB Direct), PubMed (NLM), and Web of Science (core collections via Clarivate) databases on November 18, 2020.The complete search terms and strategies are included as supplemental information.We filtered search results for English language and journal articles only; editorials and letters were excluded in each database.In addition, where applicable, we also sought conference abstracts and reviews if we felt that there were sufficient data points within the abstract.During the search process, if there were fewer than five records retrieved, filters such as English language and article type were not applied.
All records (278) were imported into Covidence (Melbourne, Australia), and duplicate citations were removed by Covidence prior to the review.Fifty-four duplicates were removed, and 224 records were set to be screened.Records were eligible for inclusion if they contained demographic and bite-related data regarding one or more patients who were envenomated by a snake species native to North America and were diagnosed with compartment syndrome.One resident and two medical toxicologists reviewed the records, and a third medical toxicologist resolved records in dispute.Results are presented in descriptive and tabular format.No formal statistical analyses were performed.

RESULTS
After initial screening of the 224 records retrieved, 161 studies were deemed irrelevant, usually due to bites from animals other than snakes, envenomation by a non-native species of snake, or bites that took place outside the United States.Upon review of the complete articles, we excluded an additional 44 due to absence of significant documented outcome measures, leaving 19 studies for study inclusion (Figure).Of the 19 studies included, 10 were single-or two-patient case reports providing patient-level data [11][12][13][14][15][16][17][18][19][20] (Tables 1-3) and nine were chart review summaries providing summary statistics of the included patients 5,21-28 (Table 4).All species causing VICS in this review fall under the Crotalinae subfamily (crotalids).In total, 88 cases were extracted: 12 from single-or two-patient case reports, and 76 cases from retrospective chart reviews.
Signs and symptoms reported included the following: rapid progression of swelling and edema (11/12, 92%); firm compartments (10/12, 83%); and pain (9/12, 75%).Erythema was not as commonly reported (3/1225%, Table 2).Compartment pressures were reported for all 12 patients, with a median compartment pressure of 60 millimeters of mercury (interquartile range [IQR] 55-68).All patients received antivenom.In six (50%) cases the authors did not specify which antivenom was used.For analytic purposes, we assumed that case reports from the 1980s and 1990s [11][12][13] employed ACP and that another report from 2011 17 used FabAV.In cases employing ACP, the median number of vials employed was 10 (IQR 7-15) and in cases employing FabAV the median was 21 (IQR 15-32).Fasciotomy was performed in 8/12 (66%) cases: 3/5 ACP and 4/6 FabAV (Table 3).With both antivenoms, patients undergoing fasciotomy received fewer vials than those who did not receive surgical management, keeping in mind the small number of patients in each group.Two patients who underwent fasciotomy reported motor deficits, compared to zero patients treated with medical therapy alone.
Chart review publications included data from 947 patients (Table 4).Three (33%) studies reported the snake species involved.Eight (89%) reported the location of bite.Only one (11%) study reported physical examination findings.Four (33%) studies reported specific compartment pressures.In total, 49 (5.2%) patients were diagnosed with compartment syndrome, and 44 of those patients underwent fasciotomy.Of patients who received fasciotomies, only six (12%) had objective compartment pressures reported.Although the chart reviews inconsistently reported which antivenom was used, it was assumed that publications from before 2001 employed ACP.The incidence of compartment syndrome in chart reviews from the ACP era was 8.3% (42 compartment syndrome diagnoses from 508 cases) compared to 1.6% (seven compartment syndrome diagnoses from 439 cases) after 2001.The number of vials of antivenom administered and information regarding the temporal association between antivenom administration and fasciotomy was not consistently reported.

DISCUSSION
After an intensive screening process, we included 19 articles in this review.Most of the included retrospective cohort studies did not report individual patient-level data.While the true prevalence is likely to be higher than the number of published reports, this nonetheless represents a small number in comparison to the approximately 6,000 snake envenomations occurring each year in the US. 29 clinically salient theme apparent in the data is that VICS portends better outcomes in comparison to trauma-induced compartment syndrome.In this review, only two patients from the included case reports (Table 3) were recorded to have residual motor deficits following VICS treatment, both of whom received a fasciotomy.No cases in the included published literature led to amputation or were associated with death.2][33][34] While the pathology underlying venom-induced vs traumatic compartment syndrome is very different, the expected clinical course and functional outcome are important points to address when counseling patients at the bedside.It should be noted that follow-up times reported were variable and generally quite short-on the order of days to weeks; so patients' final functional outcome(s) are unknown, identifying an important gap in the snakebite literature.
One interesting juxtaposition that became apparent during analysis was how the data differs between the articles published during the ACP and FabAV time periods.FabAV was approved for use in 2000, and the manufacture of ACP was discontinued in 2001.Looking at the case reports (Tables 1-3), four patients with compartment syndrome underwent fasciotomy in each antivenom "era": ACP and FabAV.The median number of antivenom vials employed in the ACP (pre-2001) reports was 10 vials, while the median number of vials in patients receiving FabAV was 21.The manufacturer of ACP recommended an initial dose for severe envenomation of 10-15 vials with additional antivenom as needed based upon the clinical response. 35Considering realworld experience, a retrospective study of 414 patients treated for presumed rattlesnake envenomation reported a mean dose of 38 vials. 36The prescribing information for FabAV recommends an initial dose of 4-6 vials, followed by an additional 4-6 vials if needed to gain initial control of the envenomation, and an additional two vials every six hours for 18 hours (total dose of 14-18 vials). 37Clinical experience suggests that most patients achieve control of swelling with Single-center, retrospective chart review of pediatric bite patients over a 10-year period.
2 patients developed necrosis of the tips of the digits.One patient developed compartment syndrome of the leg when antivenom administration was stopped after 5 vials due to an urticarial reaction.Anterior and posterior compartment pressures were 45 mm Hg.
Patients received an average of 12.5 vials of ACP antivenom except for one patient who received 4 vials of FabAV, then 5 vials of equine antivenom.The 2 patients with necrosis of the tips of the digits underwent limited debridement.
One patient with compartment syndrome of the leg underwent fasciotomy.
Mean hospital stay of 3 days (range 1-10).this regimen; additional dosing, when required, is typically directed toward hematotoxicity. 9,38he relatively low median ACP dose and somewhat high median FabAV dose noted in our review may reflect early discontinuation of ACP due to hypersensitivity reactions or fear of serum sickness, both of which are far less common with FabAV. 36This pattern aligns with a National Poison Data System review that revealed increased clinician use of antivenom, especially following Agkistrodon genus envenomation, after the year 2000. 29Alternately, this could indicate a premature decision to proceed with surgical management, prior to appropriate dosing of antivenom, during the ACP era.Expanding on this theme, analysis of the chart review studies (Table 4) revealed that the incidence of compartment syndrome in patients receiving ACP was 8.3% compared to 1.6% in patients receiving FabAV.While this decrease could reflect differences in the culprit snake species, or publication bias, as reports of VICS may no longer be considered novel or worthy of publication, the studies cited in Table 4 were generally comprehensive reviews of all snakebite patients evaluated by a center or physician group, not just the most interesting or severely envenomated patients.Therefore, it is plausible that the incidence of VICS may indeed be lower than prior to the introduction of FabAV, reflecting adequate control of tissue injury with appropriately dosed antivenom rather than fasciotomy.
Lastly, there was inconsistent reporting of data, particularly among the larger retrospective chart review studies.Laboratory abnormalities were also rarely reported but when they were, definitions of certain derangements such as coagulopathy and hypofibrinogenemia tended to differ between institutions precluding any analyses of or conclusions regarding these values.Although objective compartment pressure measurement prior to surgical management is the expert-recommended practice, 39,40 many studies did not record these values.Based on the data available to us we could not determine whether these values were not obtained or simply not reported in articles.

LIMITATIONS
As we conducted a scoping review, we did not perform a formal assessment of the included articles' methodologies or risk of bias. 41We had access only to published articles and did not have access to original datasets.Without access to identifying information, it is possible that some of the case reports were also included in the retrospective chart-review studies.Although we employed a systematic search strategy, it is possible that we did not cast a wide enough net and that some studies meeting inclusion criteria were missed.Additionally, we only searched for published research that included cases of diagnosed compartment syndrome and did not analyze the clinical characteristics of patients who were not diagnosed with compartment syndrome.While objective measurement of compartment pressures is recommended, compartment syndrome is ultimately a clinical diagnosis that may vary between physicians, particularly those from different specialties (eg, medical and surgical), and it is possible that the diagnosis may be over-or under-reported depending on the author of each paper.
Many data points were scarcely reported, including laboratory values, compartment pressures, and vials of antivenom administered.It was also sometimes difficult to discern the order of events, particularly the timing of evaluations and interventions including antivenom administration, measurement of compartment pressures, and fasciotomy.Also, none of the included cases used the recently introduced Crotalidae immune F(ab')2 antivenom, and we are unable to comment on its possible efficacy in VICS.These limitations highlight the importance of rigorous, prospective data collection and reporting through centralized, enduring databases such as the North American Snakebite Registry.

CONCLUSION
Compartment syndrome following North American snake envenomation is a rare disease process, and heterogeneity exists in its treatment despite global evidence discouraging fasciotomy.The seemingly increased tolerability of FabAV compared to ACP and the relatively positive short-term outcomes following suspected venominduced compartment syndrome supports liberal antivenom usage, proceeding to fasciotomy only after careful clinical assessment with compartment pressure measurement and toxicology consult.Additionally, no amputations or deaths were reported in the reviewed articles.We illuminate several significant gaps in the literature, including the need for prospective studies assessing differences in longterm outcomes between treatment modalities, as well as the ideal timing of antivenom employment and subsequent fasciotomy.

Identification of studies via databases and registers Identification Screening Included
Figure.PRISMA flow diagram.Volume 25, No. 4: July 2024 Western Journal of Emergency Medicine 653

Table 1 .
Demographics for case reports.

Table 2 .
Symptoms and compartment pressures for case reports.

Table 3 .
Treatments and outcomes for case reports.

Table 4 .
Summary statistics for cumulative data studies.
(Continued on next page) Western Journal of Emergency Medicine Volume 25, No. 4: July 2024 656 Compartment Syndrome Following Snake Envenomation Newman et al.